Balance of Phase I and Phase II Reactions
The products of phase I metabolism are potentially more toxic than the original molecules, which does not present a problem if the phase II enzymes are functioning at a rate to rapidly neutralize the phase I products as they are formed. This, however, is not always the case. Factors which increase the ratio of phase I to phase II activity can upset this delicate balance, producing harmful metabolites faster than they can be detoxified, and increasing the risk of cellular damage. Some of the factors include: diet (some foods and supplements increase phase I enzyme activity), smoking and alcohol consumption (both induce phase I), age (which can decrease phase II UGT, GST, and SULT activity), sex (premenopausal women show 30‒40% more phase I CYP3A4 activity than men or postmenopausal women), disease, and genetics.54
An illustrative (and unfortunately common) example of the consequences of phase I/phase II imbalance is toxicity caused by overdose of the analgesic acetaminophen (paracetamol)—the active ingredient in Tylenol. Acetaminophen toxicity is the most common cause of liver failure in the United States.55 With a normal therapeutic dose of acetaminophen, the drug is predominantly detoxified by the phase II UGT and SULT enzymes. A small amount of the drug is detoxified by a third mechanism: it is first transformed into the toxic metabolite NAPQI (N-acetyl-p-benzoquinoneimine) by phase I CYP enzymes; and this intermediate is detoxified by conjugation with glutathione using the phase II enzyme GST.
During acetaminophen overdose, the UGT and SULT enzymes become quickly overwhelmed. Proportionally more of the drug undergoes the third detoxification mechanism (transformation to NAPQI and conjugation by GST). Eventually, activity of the phase II GST enzyme slows as glutathione stores become depleted,56 and NAPQI is produced faster than it can be detoxified. Rising levels of NAPQI in the liver cause widespread damage, including lipid peroxidation, inactivation of cellular proteins, and disruption of DNA metabolism.57 Treatment for acetaminophen overdose involves the timely replenishment of glutathione stores through administration of the precursor amino acids for glutathione synthesis (most commonly N-acetyl cysteine).58